Retroperitoneal hemorrhage from adrenocortical carcinoma as a poor prognostic factor.

In most patients, adrenocortical carcinoma is diagnosed at an advanced stage of the disease. A sudden retroperitoneal hemorrhage may sometimes be the first symptom of the adrenal cancer. We describe four patients with adrenocortical carcinoma diagnosed during a retroperitoneal hemorrhage. A clinical analysis suggests that such a complication is a poor prognostic factor.


INtrODUctION
The detectability of adrenal cancer has significantly improved in recent years due to the development of new imaging techniques. Unfortunately, most of these tumors are identified at the locally invasive or metastatic stage (1). Rare cases manifest them selves by a sudden lumbar pain, followed by shock caused by retroperitoneal hemor rhage from a ruptured adrenal cancer. In the medical records of the Department of Endocrinology (Center for Postgraduate Medical Education, Warsaw), of 180 patients with adrenal carcinoma, there were four cases where such an incident was the first symptom of the disease.

cAsE rEPOrts case 1
A 12-year-old girl, after physical exercise at school, had a sudden pain in the right lumbar area accompanied by a brief lack of consciousness and tachycardia, followed by progressive weakness. Emergency surgery was indicated by a gradual fall in the hematocrit. A tumor of the right adrenal, 10 cm in diameter, and a retrop eritoneal hemorrhage from the right adrenal vein were the main intraopera tive find ings. The histopathological diagnosis was adrenocortical carcinoma. After the op era tion the patient felt well. However, four months later signs of Cushing's syn drome appeared (moon face, overweight, acne, purple striae, hirsutism, and hyperten sion). At admission to the Department of Endocrinology the girl was 160 cm in height and weighed 66 kg. Computed tomography (CT) revealed an abnormal mass (6 cm in size) at the upper pole of the right kidney; multiple metastatic tumors were identified in the lungs by a routine x-ray examination. An increase in the daily urinary excretion of steroids was also noted: 17-hydroxycorticosteroids (17-OHCS) -30.4 mg (normal, 2.2-7.0), 17-ketosteroids (17-KS) -44.4 mg (normal, 3.5-15.0). During a second operation (7 months after the first) the re-CASE REPORT current adrenal tumor and a metastatic mass in the omentum were removed. Therapy with aminoglutethimide (an adrenal inhibitor) was introduced -1.0 g daily for three months -together with mitotane (LYSODREN -Bristol) in a long-term program. The daily doses of mitotane ranged from 3.0 to 8.0 g. Clinical remission, associated with a return of steroid excretion to normal values (17-OHCS -3.0 mg/24 h, 17-KS -2.4 mg/24 h) and a reduction in the size and num ber of pulmonary metastatic tumors, was reached within about five months. After two years, androgenization reappeared and pulmonary as well as abdominal carcinoma tous recurrences progressed. The patient died about 2.5 years after the first surgical intervention. This patient has been registered in the IPACTR (2).

case 2
A 49-year-old woman was admitted to the Department of Endocrinology due to a recur rent adrenocortical carcinoma with invasion of the vena cava inferior and metastatic tumors in the liver. Three years previously she had been submitted to emergency surgery be cause of severe right abdominal pain followed by anemia and shock. An enormous retroperitoneal hematoma, penetrating to the peritoneal cavity (peritoneal rupture) was the initial surgical finding. After evacuation of the blood, a right-sided adrenal tumor (6 cm in diameter) and the right kidney (due to a lesion of the renal vein) were removed. Histopathologically the tumor was identified as adreno cortical carcinoma with hemorrhagic and necrotic areas. Shortly before the surgery, diabetes mellitus and hypertension were diagnosed. Normal 17-OHCS and 17-KS val ues were recorded after the operation. Mitotane was administered in doses rang ing from 3.0 to 8.0 g daily. After the first year of therapy, characterized by partial clini cal remission, the abdominal mass progressed and left-sided pulmo nary metas tatic tumors appeared. Chemotherapy (Cisplatin) was introduced, simulta neously with the administration of Mitotane, but without success. The patient died after two years of follow-up.

case 3
A young woman, aged 21 years, was admitted to our department because of a right adrenal tumor, found incidentally two weeks before, during routine ultrasono graphy after an emergency appendectomy for acute appendicitis. CT revealed a non-ho mogenous tumor of the right adrenal gland, 7 cm in size, and enlarged paracaval lymph nodes. No features of adrenal hyperfunction were observed. In hormonal ex aminations, slightly increased serum cortisol levels of 28 μg/dL (normal range: 5-25), and androstendione elevated to 475 ng/dL (normal: 85-270) were recorded. On the third day of observation the patient experienced sudden pain in the right lumbar area. A hemorrhage into the adrenal tumor was suspected and this was confirmed by three-dimensional sonography and CT (Figs. 1, 2 and 3). Surgery revealed a retrop eritoneal hemor rhage and adrenal tumor with a hemorrhagic, gelatinous focus. The size of the subse quently removed tumor was 10 × 9 × 6 cm. On histopathological ex amination, adrenocorti cal carcinoma was diagnosed, with hemorrhagic and necrotic areas constituting 50% of the tumor. Invasion of vessels and a ruptured A B capsule of the tumor were found. The patient was treated with mitotane (4.0 g daily) and che motherapy (cisplatin, vepezid). However, a large recurrent tumor was identified in the retroperitoneum following the first cycle of this therapy.
She died five months after the tumorectomy. This patient has been de scribed previously (3).

case 4
A 65-year-old woman was observed as an outpatient, admitted to our clinic (Department of Endocrinology) four weeks after emergency surgery for a retroperito neal hemorrhage, with evacuation of 3.5 L of blood and removal of a tumor of the left adrenal gland. Her past history was a sudden lumbar pain in the left side with pro gressive weakness followed within six hours by shock. CT revealed a retroperitoneal, non homogenous tumor. Histopathology identified an 11 × 8 × 4.5 cm sized adreno cortical carcinoma with large necrosis of the tumor. Hormonal measurements per formed after the surgery were within normal limits. Mitotane was administered, 4.5 g daily. Over the next six months, metastatic tumors were found in the left lung, as well as in the second lumbar vertebral body, with progressive paresis of the legs. The pa tient died two weeks after an orthopedic operation.

DIscUssION
Adrenocortical carcinoma is a rare tumor, representing approximately 0.02% of all cancers (4,5). Most patients are diagnosed in a locally advanced or metastatic stage of the disease (6), i.e., MacFarlane's classification stage III or IV (7), mainly following inci dental findings during imaging examinations. In the Department of En docrinology registry there have been 180 patients with adrenal cancer and 115 of them (64%) were diagnosed as incidentallyfound adrenal tumors (adrenal incidentalomas). Thus, less than half were diagnosed due to endocrinological manifestations. A retroperitoneal hemorrhage revealing the existence of an adrenal cancer is a life-threatening event. It is a rare complication of adrenal cancer and was not described in two recent reviews concerning the diagnosis and treatment of adrenocortical carci noma (8,9). In our observations, a sudden lumbar or abdominal pain and a progres sive decrease in the erythrocyte number, followed by shock, were the most charac teristic features of this potentially fatal event. Emergency surgery is a life-saving pro cedure in such cases.
In none of our four patients were typical somatic signs of hypercorisolism or hyperan drogenism apparent prior to the hemorrhagic incident. The development of Cushing's syndrome during the phase of carcinomatous dissemination in the patient No. 1 was a rare observation. Diabetes mellitus and hypertension preceding the hemorrhage in  the patient No. 2 were probably the first symptoms of metabolic and vascular disor ders due to adrenal carcinoma.
In all four patients the adrenal cancer followed an aggressive course, with rapid de velopment of local recurrences and distant me tastases. In case No. 3 a fulminant course of the adrenal cancer caused death within about six months following the hemorrhage, despite immediate mitotane administration and chemotherapy. Massive dissemination of neoplastic cells during such a severe vascular incident was probably responsible for the extensive local invasion and metastatic process in all of these patients.
In our experience (10) and in the opinion of others (11), stable remission may be ob tained in some patients with tumors at stages III or IV of MacFarlane's classification following mitotane administration and chemotherapy (10,11,12,13). Long-term ob serva tions of the remaining group with adrenal cancer revealed that early admini stration of mitotane, immediately after surgery, resulted in a better prognosis than the same treatment introduced with a delay of more than two months following surgery. An analysis of 59 patients treated with mitotane -out of 82 patients observed up to the year 2000 -indicated that there was 56% survival in the group of 32 patients given early treatment with mitotane vs 22% in the group of 27 patients, in which mi totane administration was delayed (12). However, mitotane did not improve the prog nosis in patients with a retroperitoneal hemorrhage in their past history.
In conclusion, a retroperitoneal hemorrhage due to an adrenocortical cancer should be considered as a bad prognostic factor.